A limitation of current therapeutic and/or diagnostic methods is that it is often not possible to deliver the therapeutic and/or diagnostic agent selectively or specifically to the appropriate tissue or cell type. In the case of diagnostic imaging of cancer, for example, current methods for tumor-specific imaging are hindered by imaging agents that also accumulate in normal tissues. With respect to therapeutic targeting, specificity also plays an important role as some therapeutics (e.g., anti-cancer therapeutics) are toxic, and delivery to non-target cells (e.g. normal cells) is preferably avoided.
Additionally, continuing with respect to cancer, a lack of targeting ligands that are capable of binding to multiple tumor types necessitates the synthesis of a wide range of active agents in order to treat and/or diagnose different tumor types. Ideally, a targeting molecule should display specific targeting in the absence of substantial binding to normal tissues, and a capacity for targeting to a variety of tumor types and stages. Finally, early diagnosis of neoplastic changes can result in more effective treatment of cancer. Thus, there exists a long-felt need in the art for methods to achieve delivery of imaging agents to tumors early in the course of tumorigenesis.
Cyclooxygenase (COX) activity originates from two distinct and independently regulated enzymes, termed COX-1 and COX-2 (see DeWitt & Smith (1988) Proc Natl Acad Sci USA 85, 1412-1416; Yokoyama & Tanabe (1989) Biochem Biophys Res Commun 165, 888-894; Hla & Neilson (1992) Proc Natl Acad Sci USA 89, 7384-7388). COX-1 is a constitutive isoform and is mainly responsible for the synthesis of cytoprotective prostaglandin in the gastrointestinal tract and for the synthesis of thromboxane, which triggers aggregation of blood platelets (Allison et al. (1992) N Engl J Med 327, 749-754). COX-2, on the other hand, is inducible and short-lived. Its expression is stimulated in response to endotoxins, cytokines, and mitogens (Kujubu at al. (1991) J Biol Chem 266, 12866-12872; Lee et al. (1992) J Biol Chem 267, 25934-25938; O'Sullivan et al., (1993) Biochem Biophys Res Commun 191, 1294-1300).
Cyclooxygenase-2 (COX-2) catalyzes the committed step in the biosynthesis of prostaglandins, thromboxane, and prostacyclin (Smith et al. (2000) Annu Rev Biochem 69, 145-182). COX-2 is not expressed in most normal tissues, but is present in inflammatory lesions and tumors (Fu et al. (1990) J Biol Chem 265, 16737-16740; Eberhart et al. (1994) Gastroenterology 107, 1183-1188). Studies by Eberhart et al. and Kargman et al. by first demonstrated that COX-2 mRNA and protein are expressed in tumor cells from colon cancer patients but not in surrounding normal tissue (Eberhart et al. (1994) Gastroenterology 107, 1183-1188; Kargman et al. (1995) Cancer Res 55, 2556-2559). COX-2 expression appears to be an early event in colon tumorigenesis because it is detectable in colon polyps (Eberhart et al. (1994) Gastroenterology 107, 1183-1188). Approximately 55% of polyps demonstrate COX-2 expression compared to approximately 85% of colon adenocarcinomas. The concept that COX-2 is expressed in malignant tumors and their precursor lesions has been extended to a broader range of solid tumors including those of the esophagus (Kandil et al. (2001) Dig Dis Sci 46, 785-789), bladder (Ristimaki et al. (2001) Am J Pathol 158, 849-853), breast (Ristimaki et al., (2002) Cancer Res 62, 632-635), pancreas (Tucker et al. (1999) Cancer Res 59, 987-990), lung (Soslow et al. (2000) Cancer 89, 2637-2645), stomach (Ristimaki et al. (1997) Cancer Res 57, 1276-1280), liver (Rahman et al. (2001) Clin Cancer Res 7, 1325-1332), head and neck (Chan et al. (1999) Cancer Res 59, 991-994), cervix (Gaffney et al. (2001) Intl J Radiat Oncol Biol Phys 49, 1213-1217), endometrium (Jabbour et al. (2001) Br J Cancer 85, 1023-1031), and skin, including melanoma (Denkert et al. (2001) Cancer Res 61, 303-308).
The expression of COX-2 in tumors appears to have functional consequences. Prostaglandins have been demonstrated to stimulate cell proliferation (Marnett (1992) Cancer Res 52, 5575-5589), inhibit apoptosis (Tsujii & DuBois (1995) Cell 83, 493-501), increase cell motility (Sheng et al. (2001) J Biol Chem 276, 18075-18081), and enhance angiogenesis in animal models (Daniel et al. (1999) Cancer Res 59, 4574-4577; Masferrer et al. (2000) Cancer Res 60, 1306-1311). COX-2 expression is dramatically elevated in rodent models of colon cancer and crossing COX-2 knockout mice into the APCMin− background (a mouse strain that is highly susceptible to the formation of spontaneous intestinal adenomas) reduces the number of intestinal tumors by ˜85% compared to APCMin− controls (DuBois et al., (1996) Gastroenterology 110, 1259-1262; Oshima et al. (1996) Cell 87, 803-809). COX-2 expression is detected in breast cancers from the subset of patients exhibiting Her-2/neu overexpression. Overexpression of COX-2 specifically targeted to the breast of multiparous rodents induces breast cancer. These findings suggest that COX-2 contributes to tumor progression so that its expression in tumor tissue plays an important functional role. In fact, high COX-2 expression in tumors is associated with poor clinical outcome (Tucker et al. (1999) Cancer Res 59, 987-990; Denkert et al. (2001) Cancer Res 61, 303-308; Kandil et al. (2001) Dig Dis Sci 46, 785-789; Ristimaki et al. (2002) Cancer Res 62, 632-635).
What are needed, therefore, are multifunctional compositions that can specifically bind to COX-2 in order to modulate a biological activity of COX-2, while concurrently delivering an active agent comprising a therapeutic and/or a diagnostic composition to a cell or tissue expressing COX-2, as well as methods for employing such compositions to image, diagnose, and/or treat disorders associated with abnormal proliferation of such cells and/or tissues.
To address this need, the presently disclosed subject matter provides methods and compositions for treating, diagnosing, and/or imaging COX-2-expressing cells including, but not limited to neoplastic cells and their normal and/or pre-neoplastic precursors.